The invention relates to pharmaceutical compositions and methods for the treatment of vascular disease and other diseases either resulting from, aggravated by or associated with infection by Chlamydia pneumoniae, other Chlamydia species and similar susceptible microorganisms.
Vascular disease remains a major cause of morbidity and mortality worldwide. The development of atheromatous plaque within vessel walls followed by complications such as plaque rupture with activation of the clotting cascade and occlusion of the vessel resulting in infarction of distant tissue accounts for the majority of myocardial infarction, ischaemic stroke and other ischaemic tissue injury. Conventional therapy for vascular disease seeks to prevent or reverse clot formation or to reduce vascular disease risk factors such as dyslipidaemia or hypertension. Chlamydia pneumoniae is a recently described microorganism, which has been identified in atherosclerotic plaque and incriminated in vascular disease. It is an obligate intracellular pathogen that grows within macrophages and endothelial cells. Infection with C. pneumoniae is characterised by intracellular persistence following infection. Approximately 50% of the population are seropositive for C. pneumoniae in adult life and most persons acquire the infection by the respiratory route. Not all persons infected with C. pneumoniae develop vascular disease, however. Recovery rates of the microorganism have ranged between 20 to 60% of sites of atherosclerotic tissue and the organism has not been recovered from normal vascular tissue. Animal models have been developed in which infection with C. pneumoniae is followed by the development of atherosclerotic plaque. To date, however, Koch""s postulates have not been fulfilled for C. pneumoniae in human atherosclerotic vascular disease, and this is in part a consequence of the serious nature of challenge testing as well as the fact that the organism is an obligate intracellular pathogen. Two limited therapeutic studies have been published in which there appears to be a benefit after monotherapy with a macrolide antibiotic. In one of these studies (Gupta S, et al., Circulation 1997, 96, 404-407) azithromycin was used, and the benefit was not sustained after initial therapy. In the other study (Gurfinkel E, et al., Lancet 1997, 350, 404-407) roxithromycin was used as sole therapy and in limited numbers a benefit was described, although prolonged follow-up has not yet been reported. In another study (Sinisalo J, et al., J. Antimicrob. Chemother. 1998, 41, 85-92) tetracycline antibiotics were used as monotherapy and no clinical benefit was discerned.
In the case of xe2x80x9cdifficult to eradicatexe2x80x9d intracellular pathogens, widespread use of single antibiotic regimes has serious potential adverse consequences for the population at large as well as for individuals who may develop resistant infections. Important examples of these problems in other areas of clinical practice include tuberculosis, leprosy and Helicobacter pylori infections. A further feature of largely intracellular infections such as those in which combination regimes have come to be used relates to the concept of xe2x80x9csuppressionxe2x80x9d versus xe2x80x9ceradicationxe2x80x9d following treatment. Although a course of macrolides in the treatment of C. pneumoniae can result in seemingly measurable early improvement clinically, the patients remain at risk of developing a recrudescence of the intracellular infection which has been merely suppressed rather than eradicated. With regrowth of the bacteria, the disease returns and the likelihood of response to repeated therapy is diminished, with the spectre of antimicrobial resistance. Furthermore, widespread use of single antibiotic regimes may result in greater resistance amongst C. pneumoniae and other important human pathogens than those being treated. Until now it has not been realised that antibiotic monotherapy which could result in a transient improvement in clinical parameters, was actually an indication of the suppression of the bacterial growth, with probable entry of the bacteria into a more intracellular yet chronic phase of infection.
There is therefore a need for methods of treating conditions associated with infection by C. pneumoniae and similar susceptible microorganisms which treat the initial infection so as to prevent the chronic phase of infection with its consequences of ongoing disease and heightened bacterial resistance.
The present inventors have found that a multi-drug therapy regimen is well tolerated and has a superior clinical efficacy in resolution of infections caused by Chlamydia species and similar susceptible microorganisms, and particularly C. pneumoniae, compared to monotherapy. Indeed, the method of treatment of the present invention is more likely to cure the infection rather than simply suppress it and is more likely to prevent the development of resistant isolates.
The use of multiple antibiotics for C. pneumoniae infection had not been studied prior to the date of the present invention. Experts in the field who have initiated clinical trials before and after the date of the present invention have only used single agent regimes. Prior to the date of the present invention, it had not been considered necessary or desirable to use multiple antibiotic regimes for the treatment of Chlamydia pneumoniae, other Chlamydia species and similar susceptible microorganisms. Furthermore, although there have been therapies for such infections in the past which have been considered adequate in the past, the present inventors have observed that with the passage of time there has been a change of bacterial susceptibility in communities towards more xe2x80x9cdifficult-to-curexe2x80x9d infections requiring the invention and development of more aggressive, yet safe, therapies. It is an object of the present invention to provide one such improved therapy.
Accordingly, in a first embodiment the present invention provides a method for the treatment or prevention of a condition associated with infection by Chlamydia species or similar susceptible microorganisms in a patient in need of such treatment or prevention, the method comprising the administration to the patient of an effective amount of at least two different antibiotics or antimicrobial agents selected from the group consisting of tetracyclines, macrolides, quinolones, chloramphenicol, rifamycins, sulfonamides, co-trimoxazole and oxazolidinones.
Throughout the present specification, xe2x80x9csimilar susceptible microorganismsxe2x80x9d are defined as including other difficult to culture, xe2x80x9catypicalxe2x80x9d agents such as Mycoplasma species, Listeria species, Bartonella species, and the aetiologic agents of Leptospirosis and Q fever.
The present invention also provides the use of at least two different antibiotics or antimicrobial agents selected from the group consisting of tetracyclines, macrolides, quinolones, chloramphenicol, rifamycins, sulfonamides, co-trimoxazole and oxazolidinones for the manufacture of a medicament for the treatment or prevention of a condition associated with infection by Chlamydia species or similar susceptible microorganisms in a patient in need of such treatment.
The present invention further provides at least two different antibiotics or antimicrobial agents selected from the group consisting of tetracyclines, macrolides, quinolones, chloramphenicol, rifamycins, sulfonamides, co-trimoxazole and oxazolidinones, when used for the treatment or prevention of a condition associated with infection by Chlamydia species or similar susceptible microorganisms in a patient in need of such treatment.
In a second embodiment, the invention provides a pharmaceutical composition for the treatment or prevention of a condition associated with infection by Chlamydia species or similar susceptible microorganisms in a patient in need of such treatment or prevention, the pharmaceutical composition comprising at least two different antibiotics or antimicrobial agents selected from the group consisting of tetracyclines, macrolides, quinolones, chloramphenicol, rifamycins, sulfonamides, co-trimoxazole and oxazolidinones.
In a third embodiment, the invention provides a pharmaceutical composition comprising a first antibiotic or antimicrobial agent and at least a second antibiotic or antimicrobial agent wherein at least one of said antibiotics or antimicrobial agents is provided with a pharmaceutically acceptable coating, said antibiotics or antimicrobial agents being selected from the group consisting of tetracyclines, microlides, quinolones, chloramphenicol, rifamycins, sulfonamides, co-trimoxazole and oxazolidinones.
In a fourth embodiment, the invention provides a process for preparing a pharmaceutical composition, the process comprising providing a first antibiotic or antimicrobial agent with a first pharmaceutically acceptable coating and providing at least a second antibiotic or antimicrobial agent, optionally with a second pharmaceutically acceptable coating, and incorporating the coated first antibiotic or antimicrobial agent and the optionally coated second antibiotic or antimicrobial agent into a single dosage form, said antibiotics or antimicrobial agents being selected from the group consisting of tetracyclines, macrolides, quinolones, chloramphenicol, rifamycins, sulfonamides, co-trimoxazole and oxazolidinones.
The invention also provides a pharmaceutical composition when prepared by the process of the fourth embodiment.
In further embodiments, the invention provides a method of the first embodiment which further includes the administration of a third, or a third and a fourth, or a third, a fourth and one or more further different antimicrobial agents or antibiotics. Similarly, the invention provides a pharmaceutical composition of the second embodiment which includes a third, or a third and a fourth, or a third, a fourth and one or more further different antimicrobial agents or antibiotics.